1. Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23.
- Author
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Lee JYW, Hsu CK, Michael M, Nanda A, Liu L, McMillan JR, Pourreyron C, Takeichi T, Tolar J, Reid E, Hayday T, Blumen SC, Abu-Mouch S, Straussberg R, Basel-Vanagaite L, Barhum Y, Zouabi Y, Al-Ajmi H, Huang HY, Lin TC, Akiyama M, Lee JYY, McLean WHI, Simpson MA, Parsons M, and McGrath JA
- Subjects
- Amino Acid Sequence, Animals, Apoptosis genetics, Asian People genetics, Chromosomes, Human, Pair 1 genetics, Exons, Facies, Female, Fibroblasts cytology, Fibroblasts metabolism, Genetic Linkage, Genetic Loci, Genome-Wide Association Study, Homozygote, Humans, Keratinocytes cytology, Keratinocytes metabolism, Male, Melanocytes cytology, Melanocytes metabolism, Mice, NIH 3T3 Cells, Pedigree, Pigmentation Disorders diagnosis, Spastic Paraplegia, Hereditary diagnosis, Vitiligo diagnosis, Young Adult, Pigmentation Disorders genetics, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Sequence Deletion, Spastic Paraplegia, Hereditary genetics, Vitiligo genetics
- Abstract
SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24-q32. By using whole-exome sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3' UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with fibroblast growth factor. Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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